Aminophenyl derivatives as selective androgen receptor modulators

• US 20060173037A1
• Filed: 02/06/2006
• Published: 08/03/2006
• Est. Priority Date: 01/10/2005
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Olsson, Roger, Thygesen, Mikkel Boas, Schlienger, Nathalie, Lund, Birgitte Winther, Badalassi, Fabrizio, Pawlas, Jan, Lewinsky, Rasmus
• Application Number:
  US11/348,929
• Publication Number:
  US 20060173037A1
• Time in Patent Office: Days
• US Class Current: 514/304
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: C07D 451/02 containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 451/06 Oxygen atoms

Abstract

Disclosed herein is a novel class of aminophenyl compounds having the structure:
wherein R₁ is cyano or nitro and ring A is a bi- or tricyclic bridged heterocycle and to their use as modulators of androgen receptor for the treatment or prevention of conditions relating thereto.

Claims

1. A compound represented by formula (I):

2. The compound of claim 1, wherein ring A is a bicyclic heterocycle.

3. The compound of claim 2, wherein the bicyclic heterocycle is a bridged bicyclic heterocycle.

4. The compound of claim 3, wherein:

Z₁ and Z₂ are independently selected from the group consisting of hydrogen, unsubstituted —

(C₁-C₄)alkyl, —

(C₁-C₄)alkylOH, —

(C₁-C₄)alkyl(halo), halo, cyano, —

OR₄, —

OC(O)R₄, —

CF₃, —

CHO and —

CH═

NOR₄;

R₆ and R₇ are independently selected from the group consisting of hydrogen, unsubstituted —

(C₁-C₄)alkyl, —

(C₁-C₄)alkylOH, —

(C₁-C₄)alkyl(halo), halo, cyano, —

OR₄, —

OC(O)R₄ and —

CF₃;

the bridged bicyclic heterocycle comprises one nitrogen atom; and

,

R₄ is selected from the group consisting of hydrogen, unsubstituted (C₁-C₄)alkyl, unsubstituted (C₃-C₆)cycloalkyl and unsubstituted aryl.

5. The compound of claim 4, wherein the bridged bicyclic heterocycle has the structure:

6. The compound of claim 4, wherein the bridged bicyclic heterocycle has the structure:

7. The compound of claim 6, wherein R₆ is hydroxy.

8. The compound of claim 7, wherein R₇ is —

(C₁-C₄)alkyl.

9. The compound of claim 8, wherein R₇ is bonded to the same carbon atom to which R₆ is bonded.

10. The compound of claim 1, wherein Z₁ is alkyl, halogen, haloalkyl or hydroxyalkyl.

11. The compound of claim 1, wherein Z₂ is alkyl, halogen, haloalkyl or hydroxyalkyl.

12. The compound of claim 1, wherein Z₁ is methyl or ethyl and Z₂ is halogen.

13. The compound of claim 1, wherein Z₁ is methyl or ethyl and Z₂ is chloro.

14. The compound of claim 1, wherein Z₁ is methyl, and Z₂ is chloro.

15. The compound of claim 1, selected from the group consisting of:

endo-8-(3-chloro-2-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbenzonitrile;

6-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methyl-3-nitrobenzoic acid;

3-Bromo-2-chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitrile;

2-(trifluoromethyl)-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)benzonitrile endo-8-(2,3-Dimethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-iodobenzonitrile;

2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitrile

endo-8-[2-(hydroxymethyl)-3-methyl-4-nitrophenyl]-8-azabicyclo[3.2.1]octan-3-ol;

4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-trifluoromethylbenzonitrile;

endo-8-(2-Chloro-3-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-6-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-nitrobenzaldehyde;

endo-8-(3-Chloro-2-hydroxymethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-6-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-nitrobenzaldehyde oxime;

endo-8-(2-Chloro-3-hydroxymethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

6-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methyl-3-nitrobenzoic acid;

endo-8-(2-Hydroxymethyl-3-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-methylbenzonitrile;

2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-methylbenzonitrile hydrochloride; and

,

2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-methylbenzonitrile mesylate.

16. A prodrug ester, carbonate, carbamate, sulfate, phosphate or phosphoramidate of the compound of claim 1.

17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

18. A method of treating a condition selected from the group consisting of hypogonadism, lower than normal testosterone plasma levels, infertility in males, erectile dysfunction in males, andropause in males, endometriosis in females, dyspareunia in females, vaginismus in females, sexual arousal disorders in females, sexual orgasmic disorders in females, disorders of libido in males, cachexia, HIV wasting, critical illnesses in which muscle wasting is apparent, sarcopenia, frailty, short stature, dwarfism, bone density loss, mood disorders, depression, impaired cognitive functions, neurodegenerative disorders, xerophthalmia, metabolic disorders, autoimmune disease, cardiovascular disorders, obesity, anemia, burns, prostate cancer, and schizophrenia, comprising administering to a subject exhibiting one or more symptoms of said condition a compound of claim 1.

19. The method of claim 18, wherein said mood disorder is selected from the group consisting of lack of well being, lack of vigor, anger, irritability, sadness, tiredness, and nervousness.

20. The method of claim 18, wherein said neurodegenerative disorder is selected from the group consisting of Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Mild cognition impairment (MCI), Lewis body dementia, and frontal temporal dementia.

21. The method of claim 18, wherein said metabolic disorder is selected from the group consisting of dyslipidemia, atherosclerosis, and non-insulin dependent diabetes (NIDDM).

22. The method of claim 18, wherein said cardiovascular disorder is selected from the group consisting of hypertension, coronary artery disease, and myocardial perfusion.

23. The method of claim 18, wherein the autoimmune disease is multiple sclerosis.

24. A method of modulating spermatogenesis in males, comprising administering to a male subject in need thereof a compound of claim 1.

25. A method of hormonal replacement therapy, comprising administering to a subject in need of hormonal replacement therapy a compound of claim 1.

26. The method of claim 25, wherein need for hormonal replacement therapy is caused by orchiectomy by surgical or chemical means.

27. A method of improving muscle strength comprising administering to a subject in need thereof a compound of claim 1.

28. The method of claim 27, wherein need for improvement in muscular strength is caused by muscular dystrophy, myotonic dystrophy, glucocorticoid-treated asthma or Kennedy'"'"'s disease.

29. A method of preventing a condition selected from the group consisting of bone density loss, xerophthalmia, metabolic disorders, cardiovascular disorders, obesity, and prostate cancer, comprising administering to a subject in need thereof a compound of claim 1.

30. The method of claim 29, wherein said metabolic disorder is selected from the group consisting of dyslipidemia, atherosclerosis, and non-insulin dependent diabetes (NIDDM).

31. The method of claim 29, wherein said cardiovascular disorder is selected from the group consisting of hypertension, coronary artery disease, and myocardial perfusion.

32. A method of improving a health-related quality of life parameter selected from the group consisting of survival, impairment, functional status, health perception, and opportunities, comprising administering to a subject in need thereof a compound of claim 1.

33. A method of delaying the progression of prostate cancer, comprising administering to a subject in need thereof a compound of claim 1.

34. A method of treating burns, comprising administering to a subject in need thereof a compound of claim 1.

35. A method of modulating an androgen receptor comprising contacting the receptor with a compound of claim 1.

37. The method of claim 18, wherein the subject is a mammal.

38. The method of claim 37, wherein the mammal is a human.

36. A method of:

treating a condition selected from the group consisting of hypogonadism, lower than normal testosterone plasma levels, infertility in males, erectile dysfunction in males, andropause in males, endometriosis in females, dyspareunia in females, vaginismus in females, sexual arousal disorders in females, sexual orgasmic disorders in females, disorders of libido in males, cachexia, HIV wasting, critical illnesses in which muscle wasting is apparent, sarcopenia, frailty, short stature, dwarfism, bone density loss, mood disorders, depression, impaired cognitive functions, neurodegenerative disorders, autoimmune disease, xerophthalmia, metabolic disorders, cardiovascular disorders, obesity, anemia, burns, prostate cancer, and schizophrenia;

or

modulating spermatogenesis in males;

or

effecting hormonal replacement therapy;

or

improving muscle strength;

or

preventing a condition selected from the group consisting of bone density loss, xerophthalmia, metabolic disorders, cardiovascular disorders, obesity, and prostate cancer;

or

improving a health-related quality of life parameter selected from the group consisting of survival, impairment, functional status, health perception, and opportunities;

or

delaying the progression of prostate cancer;

or

modulating an androgen receptor,

comprising administering to a subject in need thereof a compound selected from the group consisting of;

39. The method of claim 36, wherein the subject is a mammal.

40. The method of claim 39, wherein the mammal is a human.